Process for producing steroidal 7α-acylthio-4-en-3-ones

ABSTRACT

A steroidal 7α-acylthio-4-en-3-one is produced by adding a thiocarboxylic acid to a steroidal 4,6-dien-3-one in the presence of a strong acid in a neutral organic solvent.

This application is a continuation-in-part of application Ser. No.882,225 filed Feb. 28, 1978, now abandoned.

BACKGROUND OF THE INVENTION

1. Field of the Invention

This invention relates to a process for producing steroidal7α-acylthio-4-en-3-ones. More particularly, this invention relates to acommercially practical process for producing steroidal7α-acylthio-4-en-3-ones such as7α-acetylthio-17-hydroxy-3-oxo-17α-pregn-4-ene-21-carboxylic acidγ-lactone (hereinafter referred to as "spironolactone") which is atherapeutically effective antialdosteronic diuretic.

2. Description of the Prior Art

It is already known that the addition of a thiol or thiocarboxylic acidto an olefin can be accelerated with either light or a radical initiatorsuch as a peroxide or azobisisobutyronitrile. For the addition of athiocarboxylic acid to a steroidal 4,6-dien-3-one, however, such radicalinitiators have been found to exert little effect on acceleration of thereaction.

The above-mentioned spironolactone which is one of the steroidal7α-acylthio-4-en-3-ones is usually prepared by reacting17-hydroxy-3-oxo-17α-pregna-4,6-diene-21-carboxylic acid γ-lactone witha large excess of thioacetic acid under heating. According to thisprocedure, the 7β-acetylthio derivative which is therapeuticallyinactive is also produced as a by-product in approximately 25% yield,while the therapeutically active 7α-acetylthio derivative is obtained ina yield as low as 70%.

It is known from Japanese Patent Laying-Open Publication No. 4020/71that the 7α-acetylthio derivative can be obtained in approximately 90%yield with methanol being used as a solvent but without the use ofstrong acid. In this procedure, however, 5 to 10% by-products are alwaysformed in addition to the 7α- and 7β-acetylthio derivatives andtherefore it is impossible to obtain the desired 7α-acetylthioderivative in a yield exceeding 90%.

An article by Schaub et al., J. Org. Chem., 26, 3915-3925 (1961),discloses the formation of 7α-alkylthio and 7α-acylthio steroid hormonederivatives by addition to steroidal 4,6-dien-3-ones. Some examplesshowed the use of HCl in glacial acetic acid, but the yields were onlymoderate. The best yield was 61% for the formation of7α-acetylthiotestosterone acetate.

A need therefore continues to exist for a method of forming steroidal7α-acylthio-4-en-3-ones in high yield without formation of side productsother than the epimeric 7β-acylthio derivatives.

SUMMARY OF THE INVENTION

Accordingly, one object of this invention is to provide process suitablefor commercial-scale production of steroidal 7α-acylthio-4-en-3-oneswhich permits the reaction rate to be increased and suppresses theformation of by-products other than the 7α- and 7β-acylthio derivatives.Another object of this invention is to increase the ratio of 7α-acylthioderivative to 7β-acylthio derivative formed so as to obtain the desired7α-derivative in higher yields.

Briefly, these objects and other objects of the invention as hereinafterwill become more readily apparent can be attained by providing a processfor preparing steroidal 7α-acylthio-4-en-3-ones by the addition of athiocarboxylic acid to a steroidal 4,6-dien-3-one, characterized byeffecting the reaction in the presence of a strong acid in a neutralorganic solvent.

DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

The steroidal 4,6-dien-3-ones which are used as starting materials forthe process of this invention include17-hydroxy-3-oxo-17α-pregna-4,6-diene-21-carboxylic acid γ-lactone,androsta-4,6-diene-3,17-dione, 17β-acetoxyandrosta-4,6-dien-3-one,1α,2α-methylene-17β-acetoxyandrosta-4,6-dien-3-one,17α-methyl-17β-acetoxyandrosta-4,6-dien-3-one and the like.

The thiocarboxylic acids to be added to the steroidal 4,6-dien-3-onesinclude thioacetic acid, thiopropionic acid, thiobenzoic acid and thelike. The amount of the thiocarboxylic acid to be used is in the rangeof 1.1 to 20 moles, preferably 1.5 to 7 moles, per mole of the steroidal4,6-dien-3-one.

The therapeutically useful spironolactone can be obtained by thereaction of 17-hydroxy-3-oxo-17α-pregna-4,6-diene-21-carboxylic acidγ-lactone with thioacetic acid. The strong acids which are used inaccordance with the process of this invention are intended to includethose acids having higher acidity than that of the thiocarboxylic acid.Exemplary of such strong acids are sulfonic acids such asmethanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid andtrifluoromethanesulfonic acid: halo-substituted carboxylic acids such astrifluoroacetic acid and trichloroacetic acid; and inorganic acids suchas sulfuric acid, nitric acid, perchloric acid and hydrochloric acid.The most preferred strong acid is p-toluenesulfonic acid. Theconcentration of the strong acid is in the range of 0.6 to 0.003mole/liter, preferably 0.1 to 0.006 mole/liter.

The addition reaction of a thiocarboxylic acid to a steroidal4,6-dien-3-one may be carried out at a temperature of 10° to 120° C.,preferably 30° to 100° C. and more preferably 50° to 85° C.

The reaction involved in the process of this invention is carried out inthe presence of a neutral organic solvent. Suitable solvents includehydrocarbon solvents, ethers and the like. Especially preferred solventsare benzene, tetrahydrofuran and dioxane. As previously mentioned, inthe prior art processes in which no strong acid is added, the reactionrate is extremely low and it is very difficult to obtain a conversion of95% or higher. Moreover, if the reaction is carried out with anincreased amount of a thiocarboxylic acid or for a prolonged period oftime in order to increase the reaction rate or conversion, the prior artprocesses suffer the disadvantage that large amounts of by-products areformed in addition to the 7-acylthio derivatives.

In accordance with the process of this invention, the addition of thestrong acid makes possible a higher reaction rate with the avoidance offormation of by-products.

The 7-acylthio derivatives are a mixture of the 7α-acylthio derivativeand the 7β-acylthio derivative, from which the therapeutically active7α-acylthio derivative can readily be isolated by a simple purificationprocedure such as recrystallization. As the therapeutically inactive7β-acylthio derivative is readily converted to the starting steroidal4,6-dien-3-one in a high yield under basic conditions, the avoidance ofthe formation of by-products makes the process of this inventioneconomically attractive in the sense that the yield of the desired7α-acylthio derivative is increased.

An additional advantage of the process of this invention which wasentirely unexpected is that the 7β-acylthio derivative is isomerized tothe 7α-acylthio derivative in the presence of a strong acid.

The following examples, comparative examples and reference examples arepresented to further illustrate this invention but are not intended tolimit the scope thereof.

EXAMPLE 1

A mixture of 15.0464 g (44.19 mmole) of17-hydroxy-3-oxo-17α-pregna-4,6-diene-21-carboxylic acid γ-lactone, 45ml of benzene and 0.5962 g (3.46 mmole) of p-toluenesulfonic acid isheated to 75° C. in an atmosphere of nitrogen. To this mixture 9.00 g(118.3 mmole) of thioacetic acid is added and stirring is continued fortwo hours. Upon cooling to room temperature, 105 ml of aqueous saturatedsodium bicarbonate solution is added and stirring is continued for anadditional 30 minutes. The benzene layer is separated and concentrated,yielding 21.099 g of white crystals. The liquid-chromatographic analysisof these crystals shows that they contain 16.992 g (40.79 mmole; 92.3mol % yield) of7α-acetylthio-17-hydroxy-3-oxo-17α-pregn-4-ene-21-carboxylic acidγ-lactone and 1.381 g (3.31 mmole; 7.5 mol % of7β-acetylthio-17-hydroxy-3-oxo-17α-pregn-4-ene-21-carboxylic acidγ-lactone.

COMPARATIVE EXAMPLE 1

A mixture of 5.00 g (14.7 mmole) of17-hydroxy-3-oxo-17α-pregna-4,6-diene-21-carboxylic acid γ-lactone and15 ml of benzene is heated to 75° C. in an atmosphere of nitrogen. Tothe mixture is added 3.0 g of thioacetic acid and stirring is continuedfor two hours. Upon cooling to room temperature, 30 ml of aqueoussaturated sodium bicarbonate solution is added and stirring is continuedfor an additional 30 minutes. Thereafter the benzene layer is separated.According to the liquid-chromatographic analysis of the benzenesolution, 1.617 g (3.88 mmole; 26.4% yield) of7α-acetylthio-17-hydroxy-3-oxo-17α-pregn-4-ene-21-carboxylic acidγ-lactone and 0.270 g (0.646 mmole; 4.4% yield) of7β-acetylthio-17-hydroxy-3-oxo-17α-pregn-4-ene-21-carboxylic acidγ-lactone are obtained, while 3.183 g (9.35 mmole; 63.6% recovery) ofthe starting 17-hydroxy-3-oxo-17α-pregna-4,6-diene-21-carboxylic acidγ-lactone is recovered.

EXAMPLE 2

To a mixture of 5.0 g of17-hydroxy-3-oxo-17α-pregna-4,6-diene-21-carboxylic acid γ-lactone, 15ml of tetrahydrofuran and 0.20 g of p-toluenesulfonic acid which hasbeen heated at 60° C. in an atmosphere of nitrogen, 3.0 g of thioaceticacid is added and stirring is continued for an hour. Upon cooling, theresulting reaction solution is subjected to liquid-chromatographicanalysis. It is found that 7α- and7β-acetylthio-17-hydroxy-3-oxo-17α-pregn-4-ene-21-carboxylic acidγ-lactones are obtained in yields of 78.8 mol % and 16.8 mol %,respectively, and that 4.0% of the starting17-hydroxy-3-oxo-17α-pregna-4,6-diene-21-carboxylic acid γ-lactone isrecovered.

COMPARATIVE EXAMPLE 2

The procedure of example 2 is repeated except that the addition ofp-toluenesulfonic acid is omitted. The analysis shows that 7α- and7β-acetylthio-17-hydroxy-3-oxo-17α-pregn-4-ene-21-carboxylic acidγ-lactones are obtained in yields of 54.9 mol % and 12.6 mol %,respectively, and that 27.5 mol % of the starting17-hydroxy-3-oxo-17α-pregna-4,6-diene-21-carboxylic acid γ-lactone isrecovered.

EXAMPLE 3

The reaction is conducted in exactly the same manner as described inExample 1, while the change of products with the lapse of reaction timeis investigated. The results are summarized in Table 1 below.

                  Table 1                                                         ______________________________________                                                                 Yield of product (%)                                 Reaction time                                                                 (hr)       % Conversion  α-SPL*                                                                             β-SPL**                              ______________________________________                                        0.5        96.5          82.0       14.5                                      1.5        98.5          87.0       11.0                                      2.0        100.0         92.3        7.5                                      ______________________________________                                         *α-SPL:                                                                 7α-Acetylthio17-hydroxy-3-oxo-17β-pregn-4-ene-21-carboxylic        acid γ-lactone                                                          **β-SPL:                                                                 7β-Acetylthio17-hydroxy-3-oxo-17α-pregn-4-ene-21-carboxylic        acid γ-lactone                                                     

It is apparent that the 7β-acetylthio derivative is converted to the7α-acetylthio derivative.

REFERENCE EXAMPLE 1

To a solution of 1.827 g (4.39 mmole) of7α-acetylthio-17-hydroxy-3-oxo-17α-pregn-4-ene-21-carboxylic acidγ-lactone, 1.3507 g (3.24 mmole) of7β-acetylthio-17-hydroxy-3-oxo-17α-pregn-4-ene-21-carboxylic acidγ-lactone and 0.0949 g (0.28 mmole) of17-hydroxy-3-oxo-17α-pregna-4,6-diene-21-carboxylic acid γ-lactonedissolved in 312 ml of methanol, 19 ml of 1 N sodium hydroxide solutionis added and the mixture is stirred for 3 hours at 40° C. After thehydrolysis reaction, the reaction mixture is neutralized with aqueoushydrochloride. Methanol is then distilled off and the residue isextracted with benzene. The benzene extract is concentrated to give2.7190 g of crystals. The liquid-chromatographic analysis of thesecrystals shows that they contain 2.4091 g (7.06 mmole; 89.3% recovery)of 17-hydroxy-3-oxo-17α-pregna-4,6-diene-21-carboxylic acid γ-lactone.

REFERENCE EXAMPLE 2

To a solution of 5.00 g (14.7 mmole) of17-hydroxy-3-oxo-17α-pregna-4,6-diene-21-carboxylic acid γ-lactone in 15ml of methanol is added 3.00 g of thioacetic acid, and the mixture isreacted for 2 hours at 20° C. The above procedure is repeated, exceptthat the reaction temperature is 40° C. or 60° C. The relationshipbetween reaction temperature and composition of the product is shown inTable 2 below. It can be seen from this table that the formation ofapproximately 10% by-products whose structure is unknown is unavoidable.

                  Table 2                                                         ______________________________________                                        Reaction temp.                                                                           CRN*    α-SPL**                                                                          β-SPL**                                                                          By-products                               (°C.)                                                                             (%)     (%)      (%)     (%)                                       ______________________________________                                        20         1.3     75.2     15.1    8.4                                       40         0.3     78.3     11.5    9.9                                       60         0.0     88.4      3.7    7.9                                       ______________________________________                                         *CRN: 17Hydroxy-3-oxo-17α-pregna-4,6-diene-21-carboxylic acid           γ-lactone.                                                              **α-SPL, β-SPL: See the footnote of Table 1.                  

Having now fully described the invention, it will be apparent to one ofordinary skill in the art that many changes and modifications can bemade thereto without departing from the spirit or scope of the inventionas set forth herein.

What is claimed as new and intended to be covered by Letters Patent ofthe United States is:
 1. In a process for producing a steroidal7α-acylthio-4-en-3-one by the addition of a thiocarboxylic acid to asteroidal 4,6-dien-3-one, the improvement which comprises effecting thereaction in the presence of a strong acid in a neutral organic solvent.2. The process of claim 1, wherein said steroidal 4,6-dien-3-one is17-hydroxy-3-oxo-17α-pregna-4,6-diene-21-carboxylic acid α-lactone. 3.The process of claim 1, wherein said thiocarboxylic acid is thioaceticacid.
 4. The process of claim 1, wherein said strong acid isp-toluenesulfonic acid.
 5. The process of claim 1, wherein said neutralorganic solvent is benzene, tetrahydrofuran or dioxane.
 6. The processof claim 5, wherein said solvent is benzene.
 7. The process of claim 1,wherein the concentration of said strong acid is in the range of from0.003 to 0.6 mole/liter.
 8. The process of claim 1, wherein saidreaction is effected at a temperature of from 10° to 120° C.
 9. Theprocess of claim 8, wherein said temperature is from 50° to 85° C. 10.The process of claim 1, wherein the amount of said thiocarboxylic acidis in the range of from 1.1 to 20 moles per mole of said steroidal4,6-dien-3-one.
 11. The process of claim 10, wherein said amount is inthe range of from 1.5 to 7 moles per mole of said steroidal4,6-dien-3-one.
 12. The process according to claim 1, wherein theneutral organic solvent is selected from the group consisting ofhydrocarbons and ethers.